Pharmacogenetics is the study of the role of inheritance in variation of drug response, a variation that often results from individual differences in drug metabolism. Sulfation is an important pathway in the metabolism of many neurotransmitters, hormones, drugs and other xenobiotics. Sulfate conjugation is catalyzed by members of a gene superfamily of cytosolic sulfotransferase enzymes. It was recently agreed that "SULT" will be used as an abbreviation for these enzymes. These enzymes also are known as "PSTs" in the literature. Included among the nine cytosolic SULTs presently known to be expressed in human tissues are three phenol SULTs, SULT1A1, 1A2 and 1A3, which catalyze the sulfate conjugation of many phenolic drugs and other xenobiotics.
Biochemical studies of human phenol SULTs led to the identification of two isoforms that were defined on the basis of substrate specificities, inhibitor sensitivities and thermal stabilities. A thermostable (TS), or phenol-preferring form, and a thermolabile (TL), or monoamine-preferring form, were identified. "TS PST" preferentially catalyzed the sulfation at micromolar concentrations of small planar phenols such as 4-nitrophenol and was sensitive to inhibition by 2,6-dichloro-4-nitrophenol (DCNP). "TL PST" preferentially catalyzed the sulfation of micromolar concentration of phenolic monoamines such as dopamine and was relatively insensitive to DCNP inhibition. Weinshilboum, R. M. Fed. Proc., 45:2223 (1986). Both of these biochemically-defined activities were expressed in a variety of human tissues including liver, brain, jejunum and blood platelets. Human platelet TS PST displayed wide individual variations, not only in level of activity, but also in thermal stability. Segregation analysis of data from family studies of human platelet TS PST showed that levels of this activity as well as individual variations in its thermal stability were controlled by genetic variation. Price, P. A. et al., Genetics, 122:905-914 (1989).
Molecular genetic experiments indicated that there are three "PST genes" in the human genome, two of which, SULT1A1 (STP1) and SULT1A2 (STP2), encode proteins with TS PST-like activity, SULT1A1 (TS PST1) and SULT1A2 (TS PST2), respectively. The remaining gene, SULT1A3 (STM), encodes a protein with TL PST-like activity, SULT1A3 (TL PST). DNA sequences and structures of the genes for these enzymes are highly homologous, and all three map to a phenol SULT gene complex on the short arm of human chromosome 16. Weinshilboum, R. et al., FASEB J., 11(1):3-14 (1997).